Microstereolithography is a precision machining technology to fabricate structures of an arbitrary shape by exposing photocurable resins to laser light. In 1992, Ikuta et al., the inventors of the present invention, achieved the world's first 5 μm three-dimensional resolutions (Non-patent Literature 1). Many research studies followed and papers were published after the announcement (Non-patent Literature 2). Nano-stereolithography at sub-micro resolutions has also been developed. Recently, microstereolithography is being applied to μ-TAS for studying and analyzing chemical reactions occurring in microchannels, and to the development of MEMS devices (Non-patent Literature 3-5).
But commercial photocurable resins do not have biocompatibility, so microstereolithography has not been applied to devices that need to be in direct contact with cells or living organisms (Non-patent Literature 6-8).
To solve this problem, the inventors of the present invention decided to develop a new post process to add cytocompatibility to commercial microstereolithographic epoxy photocurable resins which already have proven stable photocurable and other characteristics. They chose this approach as it is more versatile and applicative than trying to develop new photocurable resins with the required biocompatibility, curing characteristics and accuracy.
So far, the following reports have introduced the application of microstereolithography to devices that are indirect contact with living cells or organs:
Firstly, photo initiators, which are highly cytotoxic materials, are avoided and biodegradable polymers, for example caprolactone or poly (propylene fumarate), are adopted to synthesize new photocurable resins for microstereolithography (Non-patent literature 8-11). This approach necessitates a resin synthesis and blending process. Furthermore, the approach is designed to fabricate biodegradable scaffolds for cells in tissue engineering. As such, this approach cannot be used to fabricate non-degradable devices to be used in the present invention.
Secondly, hydrogels such as polyethylene glycol are used in microstereolithography to fabricate scaffolds for cells (Non-patent Literature 7 and 13). It is possible to culture cells on hydrogel surfaces and inside hydrogels, but this method is difficult to apply to the fabrication of devices because of the insufficient strength of the hydrogels.
Furthermore, low processing accuracy due to desiccation shrinkage is a large problem, and this approach does not meet the objectives of our present research.
Thirdly, cell culturing on the surfaces of three-dimensional lattice structures made of commercial photocurable resins has been reported, however cell cultures on planar structures failed (Non-patent Literature 14).
1) Non-patent Literature: Ikuta K, Hirowatari K, Real three-dimensional microfabrication using stereo lithography and metal molding. Proceedings of the IEEE Workshop on Microelectromechanical Systems, MEMS' 93. 1993: 42-47.
2) Non-patent Literature: Bertsch A, Jiguet S, Bernhard P, Renaud P, Microstereolithography: a Review. Mat. Res. Soc. Symp. Proc. 2003, OO1.1.1-LL1.1.13
3) Non-patent Literature: Maruo S, Ikuta K, Korogi H. Submicron manipulation tools driven by light in a liquid. Appl Phys Lett 2003; 82: 133-135
4) Non-patent Literature: Kawata S, Sun HB, Tanaka T, Takada K. Finer features for functional microdevices. Nature 2001; 412: 697-698
5) Non-patent Literature: Maruo S, Ikuta K. Submicron stereolithography for the production of freely movable mechanism by using single-photon polymerization. Sensor Actuat A-phys 2002; 100: 70-76
6) Non-patent Literature: Lu, Chen SC. Micro and nano-fabrication of biodegradable polymers for drug delivery. Adv Drug Deliv Rev. 2004; 11: 1621-33
7) Non-patent Literature: Tsang VL, Bhatia S N. Three-dimensional tissue fabrication. Adv Drug Deliv Rev. 2004; 11: 1635-47
8) Non-patent Literature: Popov VK, Evseev AV, Ivanov A L, Roginski VV, Volozhin AI, Howdle SM. Laser stereolithography and supercritical fluid processing for custom-designed implant fabrication. J Mater Sci Mater Med. 2004; 2: 123-8
9) Non-patent Literature: Lee JW, Lan PX, Kim B, Lim G, Cho DW. 3D scaffold fabrication with PPF/DEF using macro-stereolithography. Microelectron Eng 2007; 84: 1702-1705
10) Non-patent Literature: Matsuda T, Mizutani M. Liquid acrylate-endcapped biodegradable poly(e-caprolacton-co-trimethyrene carbonate). II. Computer-aided stereolithographic microarchitectual surface photoconstructs. J Biomed Mater Res. 2002; 3: 395-403
11) Non-patent Literature: Lee KW, Wang S, Fox BC, Ritman E L, Yaszemski MJ, Lu L. Poly (propylene fumarate) bone tissue engineering scaffold fabrication using stereolithography: effects of resin formulations and laser parameters. Biomacromolecules. 2007; 4: 1077-84
12) Non-patent Literature: Cooke MN, Fisher JP, Dean D, Rimnac C, Mikos AG. Use of stereolithography to manufacture critical-sized 3D biodegradable scaffolds for bone ingrowth. J Biomed Mater Res B Appl Biomater. 2003; 2: 65-9
13) Non-patent Literature: Arcaute K, Mann BK, Wicker R B. Stereolithography of Three-Dimensional Bioactive Poly(Ethylene Glycol) Constructs with Encapsulated Cells. Ann Biomed Eng 2006; 34; 1429-1441
14) Non-patent Literature: Lee SJ, Kang HW, Kang TY, Kim B, Lim G, Rhie JW, Cho DW, Development of scaffold fabrication system using an axiomatic approach. J Micromech Microeng 2007; 17: 147-153
15) Non-patent Literature: Jones CE, Underwood CK, Coulson EJ, Taylor PJ. Copper induced oxidation of serotonin: analysis of products and toxicity. J Neurochem 2007; 102: 1035-1043